Nucleic acids occurring in nature are constituent components of DNA or RNA and the skeletons thereof have been used in a variety of medicines. Nucleic acids occurring in nature have a D-steric configuration and, therefore, D-nucleic acid derivatives have been used in medicines. In recent years, however, the meritorious effect of L-nucleic acid derivatives which are unnatural products, have been found and active development is under way for such L-nucleic acid derivatives. For example, clinical tests are under way using L-FMAU [1-(2′-deoxy-2′-fluoro-β-L-arabinofuranosyl)thymine], LdT [1-(β-L-arabinofuranosyl)thymine], a L-dc derivative [1-(2′-deoxy-β-L-arabinofuranosyl)cytidine derivative] or the like, and also studies are under way for processes for synthesis of such L-nucleic acid derivatives. In producing a L-nucleic acid derivative, it is necessary to use a L-saccharose as a basic skeleton and raw material for the derivative; however, this L-saccharose or a derivative thereof does not substantially occur in nature. L-arabinose is one of limited kinds of L-saccharoses occurring in nature and is available industrially. Hence, L-arabinose has generally been used as a raw material in synthesis of L-nucleic acid derivative.
In the case of, for example, L-FMAU, it is obtained by, as described in Nucleosides & Nucleotides, 18(2), 187–195 (1999), synthesizing, from L-arabinose, a corresponding L-saccharose moiety (3,5-di-O-benzoyl-1-bromo-2-deoxy-2-fluoro-β-L-arabinofuranose), reacting it with a silylated thymine, and conducting deprotection. However, there remain problems that the synthesis of L-saccharose moiety comprises 12 steps and the whole process consists of 14 steps in total and is long and that these steps comprise those difficult to conduct industrially, such as chromic acid oxidation and the like. Also in the synthesis of LdT or L-dc derivative, they are obtained by reacting a L-saccharose moiety [1-chloro-3,5-di-O-(p-chlorobenzoyl)-2-deoxy-L-ribofuranose] with a silylated thymine. This L-saccharose moiety is synthesized from L-arabinose, as described in Nucleosides & Nucleotides, 18(11), 2356 (1999); however, this synthesis comprises 9 steps and the whole process consists of 11 steps in total and is long, there are used sodium hydride, carbon disulfide, methyl iodide, diphenylsilane, etc. in the deoxy step, and thus there remain problems of safety and cost in industrial production.
Meanwhile, it is considered to apply a process which has been established by the past studies on synthesis of D-nucleic acid derivative. For example, a 2,2′-anhydro-1-(β-D-arabinofuranosyl)thymine derivative is known as an important synthesis intermediate which can be developed into a variety of D-thymidine derivatives. Of synthesis processes therefor, one having industrial applicability is a process which comprises reacting a D-ribose derivative with a thymine derivative to obtain 2′-hydroxythymidine and then subjecting it to cyclization to obtain a 2,2′-anhydro-1-(β-D-arabinofuranosyl)thymine derivative. However, in applying this process to synthesis of L-nucleic acid, L-ribose (necessary as a raw material) does not substantially occur in nature and is difficult to obtain; therefore, the above process is unapplicable to the synthesis of a 2,2′-anhydro-1-(β-L-arabinofuranosyl)thymine derivative. The following processes are also known as a synthesis process using D-arabinose as a raw material.
(1) A process which comprises subjecting, to ring closure using potassium t-butoxide, an arabinoaminooxazoline-α-bromomethylacrylic acid ester addition product obtained from arabinoaminooxazoline and an α-bromomethylacrylic acid ester to obtain 2,2′-anhydro-1-(β-D-arabinofuranosyl)thymine (JP-A-6-92988).
(2) A process which comprises reacting arabinoaminooxazoline with methyl β-bromomethacrylate in the presence of triethylamine-diethylaminopyridine to synthesize a 2,2′-anhydro-1-(β-D-arabinofuranosyl)thymine derivative (JP-A-2-59598).
(3) A process which comprises protecting the hydroxyl group of arabinoaminooxazoline with an organosilicon compound such as t-butyldimethylsilyl group or the like, then reacting the resulting compound with methyl methacrylate, and subjecting the resulting adduct to dehydrogenation using manganese dioxide or dichlorodicyanoquinone to synthesize a 2,2′-anhydro-1-(β-D-arabinofuranosyl)thymine derivative [J. Org. Chem., 60(10), 3097 (1995)].
In the process (1), however, there is formed, in a fairly large amount, a hydrolysis product of the ester moiety of D-arabinoaminooxazoline-α-bromomethylacrylic acid ester addition product, resulting in a low yield; in the process (2), the reaction time is very long and the yield is low; in the process (3), the protection of hydroxyl and a special dehydrogenating agent are necessary. Thus, any process was not at a level of industrial applicability. Therefore, in order to industrially produce a L-nucleic acid derivative for use in medicine, a novel efficient synthesis process has been required.